Oral compositions containing biphenol antibacterial compounds

ABSTRACT

Antiplaque oral compositions are provided that contain an orally acceptable carrier and an antibacterial effective amount of the compound of formula (I). In various embodiments, the compositions contain from about 0.001% to about 10% by weight of the compound of formula (I).

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/640,160, filed Dec. 29, 2004, the contents of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

A number of disease conditions are associated with the action ofbacteria in the oral cavity. For example, gingivitis, an inflammation orinfection of the gums and alveolar bones, is generally believed to becaused by plaque causing bacterial and the toxins formed as by-productsfrom the bacteria. In addition, plaque provides a locus for calculus ortartar formation. Periodontitis is generally believed to occur whereunremoved plaque hardens into calculus (tartar), which affects theperiodontal ligaments. As plaque and tartar continue to build up, thegums begin to recede, which can lead to continued inflammation,infection and potentially the loss of teeth.

To prevent or treat these diseased conditions, antibacterial agents maybe incorporated into oral care compositions such as toothpaste andmouthwashes or rinses. Application of antibacterial compositions in theoral cavity tends to retard plaque formation and related oralinfections. It is also common to provide oral compositions containingcomponents that remove or prevent the build-up of tartar. Effectiveantitartar agents, such as phosphates, are believed to work in-part byinterfering with crystalline growth of hydroxyapatite on the toothsurface.

The antiplaque efficacy of antibacterial compounds in a dentifricecomposition depends on a number of factors, including the presence ofother ingredients that may interfere with its action. For example,certain cationic antibacterial compounds and certain nonionicantibacterial compounds lose their effectiveness when formulated withcertain anionic surfactants or other anionic active ingredients, such astartar control phosphates. In many instances, it is preferred to useantibacterial compounds that do not show the adverse interactions withsuch anionic components.

Extracts from Magnolia officinalis (hereinafter “magnolia”), andespecially from the bark, contain biphenol antibacterial compounds. Theextracts have been found to have antibacterial effectiveness whenformulated into, for example, toothpaste formulations.

Extracts prepared from natural sources such as magnolia are variable incomposition and may contain many compounds other than the particularactives for which the extract is prepared. In addition, the compositionof the extracts can vary from season to season and between differentgeographical regions. For these many reasons, it may be desirable tosynthesize naturally occurring products such as those found in magnoliaextracts.

BRIEF SUMMARY OF THE INVENTION

The invention is based in part on the discovery that a particular analogof magnolol—5,5′-dibutyl-2,2′-dihydroxy-1,1′-biphenyl—is effective as anantiplaque and antibacterial component of dentifrices and other oralcompositions. The invention relates to various oral compositionscontaining the compound and an orally acceptable carrier. In variousembodiments, antibacterial and antiplaque oral compositions are providedin the form of a paste or gel, a powder, a mouthwash or mouth rinse, alozenge, chewing gum, an edible strip, and the like. The antibacterialcompound is synthesized by Friedel-Crafts type acylation of a biphenolcompound, followed by reduction to the end product.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a new antibacterial compound5,5′-dibutyl-2,2′-dihydroxy-1,1′-biphenyl represented by the structureof formula (I), given below:

wherein any/all of the carbon atoms may be independently substituted orunsubstituted.

Antiplaque oral compositions are provided that contain an orallyacceptable carrier and an antibacterial effective amount of the compoundof formula (I) are also included. In various embodiments, thecompositions contain from about 0.001% to about 10% by weight of thecompound of formula (I). Without limitation, the orally acceptablecarrier is a liquid carrier; a powder carrier; or a carrier thatdissolves upon contact with saliva and other components of an oralenvironment, such as, for example a film. In other embodiments, thecarrier can comprise a gum base. The oral compositions are providedvariously in the form of a paste or gel, a powder, a mouth rinse, alozenge, chewing gum, and an edible strip. Other forms of thecomposition include without limitation a liquid suitable for painting adental surface, a wafer, a wipe or towelette, an implant, a dentalfloss, and forms that are edible or chewable by a small domestic animalsuch as a cat.

In other embodiments, the invention provides paste or gel compositionsthat contain at least one humectant, at least one abrasive material, andan antibacterial effective amount of the compound of formula (I). Thepaste or gel compositions may further comprise an anticalculus agentsuch as a phosphate compound, alternatively combined with syntheticanionic polycarboxylates. In an exemplary embodiment, the paste or gelcomposition comprises, for example:

0.001-5% by weight of compound of formula (I);

1-70% by weight humectant;

1-70% by weight abrasive compounds;

0.5-2.5% by weight tetrasodium pyrophosphate (TSPP); and

1-10% by weight sodium tripolyphosphate (STPP).

In other embodiments, the invention provides a method for inhibitingbacterial growth in the oral cavity of a subject animal, comprisingapplying to the oral surfaces of the subject animal an antibacterialcomposition comprising the compound of formula (I). In variousembodiments, the method involves brushing the teeth, rinsing and/orapplying to the oral surfaces compositions containing the compound offormula (I). As above, the method can be practiced by applying theantibacterial composition in a wide variety of forms such as pastes,gels, powder, mouth rinse, paint on gels, dissolvable or edible stripsor films, chewing gum, lozenges, and the like.

In various embodiments, treatment of oral surfaces with antibacterialcompositions containing the compound of formula (I) leads to reductionor elimination of plaque, to prevention or treatment of gingivitis, toamelioration of oral malodor, and prevention of periodontal disease. TheMIC₅₀ of the compound of formula (I) has been found to be lower againstcertain oral bacteria than an analogous compound containing propylgroups.

The methods of preparing the compound of formula (I) include a step ofreacting 2,2′-dihydroxy-1,1′-biphenyl with a butanoyl halide, such asbutanoyl chloride, in the presence of a Lewis acid to form a carbonylfunctional intermediate. Thereafter, the carbonyl functionalintermediate is reduced to obtain the compound of formula (I).

Synthesis of the compound of formula (I) may be illustrated by thefollowing scheme:

In a first step, a 2,2′-dihydroxy-1,1′-biphenyl is reacted with analkanoyl halide (illustrated as, e.g., butanoyl chloride) containingfour carbons in the presence of a Lewis acid (illustrated as, e.g.,aluminum chloride). The reaction product is a carbonyl functionalintermediate (III). The carbonyl functional intermediate is next reducedwith conventional reducing agents to yield the final product (I). Asshown in the scheme, reduction is accomplished by refluxing in aceticacid and HCl in the presence of a zinc mercury amalgam as a reducingagent (Clemmensen reduction). Other Lewis acids can be used in the firststep, and other reducing agents can be used in the second step. Lewisacid catalysts and reducing agents and the conditions under which theycan be utilized are well known in the art, and any such compounds and/orconditions may be used. Non-limiting reduction reactions include theWolff-Kishner reduction, the Huang-Minlon modification, and reductionwith lithium aluminum hydride/aluminum chloride.

The antibacterial compound of formula (I) is formulated with an orallyacceptable carrier to provide oral compositions having a variety offorms.

The compositions of the invention contain an orally acceptable carrierand an antibacterial effective amount of the compound of formula (I).The carrier embraces all of the components of the oral compositionexcept for the antibacterial compound of formula (I). The carrier mayinclude components such as inactive ingredients, carriers, vehicles, andother active ingredients.

To illustrate in a non-limiting example for the case of pastes, thecarrier can be a water/humectant system. Alternatively, the carriercomponent of a paste composition may be water, humectant, and otherfunctional components other than the compound of formula (I). Whateverthe context, a person of skill in the art recognizes that the pastecomposition contains both antibacterial compounds of the formula (I) andan orally acceptable carrier for the compound.

In a mouth rinse, the carrier may be, for example, a water/alcoholliquid component in which the antibacterial compounds of the formula (I)are dissolved, dispersed, suspended or otherwise incorporated. In adissolvable lozenge, the carrier may be the solid matrix material thatdissolves in the mouth to the oral surfaces in the mouth. In chewinggums, the carrier may be a gum base, while in an edible strip, thecarrier may be one or more film forming polymers.

In all of the above examples, the oral composition, in whatever form,includes antibacterial compounds of the formula (I), a suitable carrierin an appropriate form, and other actives or functional materials neededto provide the oral compositions with desired properties.

In addition to the carrier, oral compositions of the invention containan antibacterial effective amount of the compound of formula (I). Theantibacterial effective amount may be preferred to be about 0.001% toabout 10%, based on the total weight of the oral composition, forexample about 0.01% to about 5% or about 0.1% to about 2%. The effectiveamount may vary depending on the form of the oral composition. Forexample, in pastes, gels, and powders, an effective amount may be atleast about 0.01% and more preferably at least about 0.05%. Preferably,the compound of the formula (I) is formulated at 5% or less, preferablyabout 2% or less, and more preferably about 1% or less.

In mouth washes and rinses, the compound of the formula (I) may be about0.001% (or 10 ppm) up to about 1%. Preferably, the compound representedby formula (I) may be present at about 0.5% or less or about 0.2%.Preferably, it is about 0.01% (100 ppm) or greater. In variousembodiments, compound represented by formula (I) is present at about0.03 to about 0.12% by weight.

In addition to the antibacterial compound of the formula (I), a numberof active ingredients and functional materials are included in variouscompositions of the invention. Such materials include, withoutlimitation, abrasives, humectants, surfactants, anticalculus agents,thickeners, viscosity modifiers, anticaries agents, flavorants,colorants, additional antibacterial agents, antioxidants,anti-inflammation components, and so on. Such components may be added tothe pastes, rinses, gums, lozenges, strips, and other forms of the oralcompositions of the invention according to known methods.

In various embodiments of the present invention, where the carrier ofthe oral care composition is solid or a paste, the oral compositionpreferably comprises a dentally acceptable abrasive material which mayserve to either polish the tooth enamel, provide a whitening effect, orremove accumulated plaque. Non-limiting examples include silicaabrasives such as silica gels and precipitated silicas. Commercialsilicas may be used, such as ZEODENT® 115, marketed by J. M. Huber andSYLODENT® XWA, SYLODENT® 783 or SYLODENT® 650 XWA of the DavisonChemical Division of W. R. Grace & Co., Princeton, N.J. Other suitabledentifrice abrasives include, without limitation, sodium metaphosphate,potassium metaphosphate, tricalcium phosphate, dihydrated dicalciumphosphate, aluminum silicate, calcined alumina, bentonite or othersiliceous materials, or combinations thereof.

The abrasive may be present in any amount, depending on the desired endresult. In embodiments where the oral composition is in a solid or pasteform, the abrasive material is generally present at about 10% to about99% of the oral composition. In certain embodiments, the polishingmaterial is present in amounts of about 10% to about 75% (for example,about 10% to about 40% or about 15% to about 30%) and from about 70% toabout 99%.

In a still further embodiment, a composition of the invention comprisesat least one humectant. Any orally acceptable humectant can be used,including without limitation polyhydric alcohols such as glycerin,sorbitol, xylitol and low molecular weight PEGs. One or more humectantsmay be present in a total amount of about 1% to about 70%, for exampleabout 1% to about 50%, about 2% to about 25%, or about 5% to about 15%by weight of the composition.

The composition of the invention may include at least one surfactantuseful, for example, to compatibilize other components of thecomposition and thereby provide enhanced stability, to help in cleaningthe dental surface through detergency, and to provide foam uponagitation, e.g., during brushing with a dentifrice composition of theinvention. Any orally acceptable surfactant, can be used. Suitablesurfactants include without limitation water-soluble salts of C₈₋₂₀alkyl sulfates, sulfonated monoglycerides of C₈₋₂₀ fatty acids,sarcosinates, taurates and the like. Illustrative examples of these andother classes include sodium lauryl sulfate, sodium coconutmonoglyceride sulfonate, sodium lauryl sarcosinate, sodium laurylisethionate, sodium laureth carboxylate and sodium dodecylbenzenesulfonate. Others include without limitation poloxamers,polyoxyethylene sorbitan esters, fatty alcohol ethoxylates, alkylphenolethoxylates, tertiary amine oxides, tertiary phosphine oxides, dialkylsulfoxides and the like. Further examples include without limitationderivatives of C₈₋₂₀ aliphatic secondary and tertiary amines having ananionic group such as carboxylate, sulfate, sulfonate, phosphate orphosphonate, such as cocoamidopropyl betaine. One or more surfactantsmay be present in a total amount of about 0.01% to about 10%, forexample about 0.05% to about 5% or about 0.1% to about 2% by weight ofthe composition.

The composition may include an orally acceptable anticalculus agent. Oneor more such agents can be present. Suitable anticalculus agents includewithout limitation phosphates and polyphosphates (for examplepyrophosphates), polyaminopropanesulfonic acid (AMPS), zinc citratetrihydrate, polypeptides such as polyaspartic and polyglutamic acids,polyolefin sulfonates, polyolefin phosphates, diphosphonates such asazacycloalkane-2,2-diphosphonates (e.g.,azacycloheptane-2,2-diphosphonic acid), N-methylazacyclopentane-2,3-diphosphonic acid, ethane-1-hydroxy-1,1-diphosphonicacid (EHDP) and ethane-1-amino-1,1-diphosphonate, phosphonoalkanecarboxylic acids and salts of any of these agents, for example theiralkali metal and ammonium salts.

Useful inorganic phosphate and polyphosphate salts illustrativelyinclude monobasic, dibasic and tribasic sodium phosphates, sodiumtripolyphosphate (STPP), tetrapolyphosphate, mono-, di-, tri- andtetrasodium pyrophosphates, disodium dihydrogen pyrophosphate, sodiumtrimetaphosphate, sodium hexametaphosphate and the like, wherein sodiumcan optionally be replaced by potassium or ammonium. Other usefulanticalculus agents include polycarboxylate polymers. These includepolymers or copolymers of monomers that contain carboxylic acid groups,such as acrylic acid, methacrylic acid, and maleic acid or anhydride.Non-limiting examples include polyvinyl methyl ether/maleic anhydride(PVME/MA) copolymers, such as those available under the GANTREZ® brandfrom ISP, Wayne, N.J., United States of America. Still other usefulanticalculus agents include sequestering agents includinghydroxycarboxylic acids such as citric, fumaric, malic, glutaric andoxalic acids and salts thereof, and aminopolycarboxylic acids such asethylenediaminetetraacetic acid (EDTA). One or more anticalculus agentsare optionally present in the composition in an anticalculus effectivetotal amount, such as about 0.01% to about 50%, for example about 0.05%to about 25% or about 0.1% to about 15% by weight.

In various embodiments, the anticalculus system comprises a mixture ofsodium tripolyphsophate (STPP) and a tetrasodium pyrophosphate (TSPP).In various embodiments, the ratio of TSPP to STPP ranges from about 1:2to about 1:4. In a preferred embodiment, the first anticalculus activeingredient, TSPP is present at about 1 to about 2.5% and the secondanticalculus active ingredient, STPP is present at about 1 to about 10%.

In various embodiments, the anticalculus system further comprises asynthetic anionic polycarboxylate polymer, present for example, in anamount of about 0.1% to about 5%. In another embodiment, the syntheticanionic polycarboxylate may be present in an amount of about 0.5% toabout 1.5%, most preferably at about 1% of the oral care composition. Inone embodiment, the anticalculus system can include a copolymer ofmaleic anhydride and methyl vinyl ether, such as for example, theGANTREZ® S-97 product discussed above.

In various embodiments, the ratio of TSPP to STPP to the syntheticanionic polycarboxylate ranges from about 5:10:1 to about 5:20:10 (or1:4:2). In one embodiment, the anticalculus system of the oral carecomposition comprises TSPP, STPP, and a polycarboxylate such as acopolymer of maleic anhydride and methyl vinyl ether at a ratio of about1:7:1. In a non-limiting embodiment, the anticalculus system consistsessentially of TSPP present at about 0.5% to about 2.5%, STPP present atabout 1% to about 10%, and a copolymer of maleic anhydride and methylvinyl ether present at about 0.5% to about 1.5%.

In a still further embodiment a composition of the invention may containa thickening agent, useful, for example, to impart a desired consistencyand/or mouth feel to the composition. Any orally acceptable thickeningagent can be used, including without limitation carbomers, carboxyvinylpolymers, carrageenans, particularly ι-carrageenan (iota-carrageenan),cellulosic polymers such as hydroxyethylcellulose,carboxymethylcellulose (CMC) and salts thereof, e.g., CMC sodium,natural gums such as karaya, xanthan, gum arabic and tragacanth,colloidal magnesium aluminum silicate, colloidal silica and the like.One or more thickening agents are optionally present in a total amountof about 0.01% to about 15%, for example about 0.1% to about 10% orabout 0.2% to about 5% by weight of the composition.

In a still further embodiment a composition of the invention may includeat least one viscosity modifier. Any orally acceptable viscositymodifier can be used, including without limitation mineral oil,petrolatum, clays and organo-modified clays, fumed silica and the like.One or more viscosity modifiers may be optionally present in a totalamount of about 0.01% to about 10%, for example about 0.1% to about 5%by weight of the composition.

In another embodiment the composition may contain a source of fluorideions. One or more such sources can be present. Suitable sources offluoride ions include fluoride, monofluorophosphate and fluorosilicatesalts, and amine fluorides, including olaflur(N′-octadecyltrimethylendiamine-N,N,N′-tris(2-ethanol)-dihydrofluoride).Any such salt that is orally acceptable can be used, including withoutlimitation alkali metal salts, and ammonium, stannous and indium salts.One or more fluoride-releasing salts are optionally present in an amountproviding a total of about 100 to about 20,000 ppm, about 200 to about5,000 ppm, or about 500 to about 2,500 ppm, fluoride ions to thecomposition. Where sodium fluoride is the sole fluoride-releasing saltpresent, illustratively an amount of about 0.01% to about 5%, about0.05% to about 1% or about 0.1% to about 0.5%, sodium fluoride by weightmay be present in the composition.

Other components suitable for inclusion in the composition include,without limitation, flavorants, colorants, and other active ingredientssuch as antioxidants and anti-inflammation agents. The components areformulated into oral compositions according to known procedures.

The orally acceptable vehicle or carrier in a lozenge bead or tablet maybe a non-cariogenic, solid water-soluble polyhydric alcohol (polyol)such as mannitol, xylitol, sorbitol, malitol, hydrogenated starchhydrozylate, hydrogenated glucose, hydrogenated disaccharides,hydrogenated polysaccharides, and the like in an amount of about 85% toabout 95% of the total composition. Emulsifiers such as glycerin, andtableting lubricants, in minor amounts of about 0.1% to 5%, may beincorporated into the tablet, bead or lozenge formulation to facilitatethe preparation of the tablet beads and lozenges. Suitable lubricantsinclude vegetable oils such as coconut oil, magnesium stearate, aluminumstearate, talc, starch and CARBOWAX®. Suitable non-cariogenic gumsinclude kappa carrageenan, carboxymethyl cellulose, hydroxyethylcellulose and the like.

The lozenge, bead or tablet may optionally be coated with a coatingmaterial such as waxes, shellac, carboxymethyl cellulose,polyethylene/maleic anhydride copolymer or kappa-carrageenan to furtherincrease the time it takes the tablet or lozenge to dissolve in themouth. The uncoated tablet or lozenge may be formulated to be slowdissolving, providing a sustained release rate of active ingredients ofabout 3 to 5 minutes. Accordingly, the solid dose tablet, bead andlozenge compositions of this embodiment affords a relatively longer timeperiod of contact of the teeth in the oral cavity with the antibacterialand anticalculus active ingredients of the present invention.

Gum base materials for use in a gum form of the composition are wellknown in the art and include natural or synthetic gum bases thereof.Representative natural gums or elastomers include chicle, naturalrubber, jelutong, balata, guttapercha, lechi caspi, sorva, guttakay,crown gum, and perillo, or mixtures thereof. Representative syntheticgums or elastomers include butadiene-styrene copolymers, polyisobutyleneand isobutylene-isoprene copolymers. The gum base is incorporated in thechewing gum product at a concentration of about 10% to about 40% andpreferably about 20% to about 35%.

The invention has been described above with respect to various preferredembodiments. Further non-limiting description is provided in thefollowing examples.

EXAMPLES Example 1

The dipropyl and dibutyl analogs of magnolol are synthesized byFriedel-Crafts acylation of 2,2′-diphenol with propanoyl chloride andbutanoyl chloride respectively, followed by Clemmensen reduction toyield 5,5′-propyl-2,2′-dihydroxy-1,1′-biphenyl and5,5′-dibutyl-2,2′-dihydroxy-1,1′-biphenyl, respectively.

Example 2

MIC₅₀ values against a variety of bacteria are measured for the dipropyland dibutyl derivatives and compared to those for triclosan. Results aregiven in Table I. Lower numeric values correspond to more effectiveantibacterial activity.

TABLE I MIC₅₀ for dipropyl MIC₅₀ for dibutyl MIC₅₀ for Bacteriaderivative derivative triclosan S. aureus >500 7.8 2 S. gordonii >50031.3 7.8 S. mutans >500 3.9 7.8 E. corrodens 1 0.5 <0.001 P. gingivalis3.9 2 0.5 A. actino. >500 >500 0.125 P. intermedia 2 2 1 P. nigresc. 7.83.9 3.9 F. nucleatum >500 >500 1 M. catarrhalis 7.8 15.6 <0.001 B.cereus >500 31.3 15.6 B. subtilis >500 7.8 2

As can be seen from Table I against a number of staphylococcus,streptococcus, and bacillus bacteria in the Table, MIC₅₀ of the compoundof formula (I) is over an order of magnitude less than that of thedipropyl derivative, and comparable to that of triclosan.

1. A dentifrice composition selected from the group consisting of atooth paste, gel, powder, a mouthwash and a mouth rinse comprising anantibacterial effective amount of a compound represented by formula (I):


2. The composition of claim 1, wherein the compound represented byformula (I) is present in an amount of about 0.001% to about 10% byweight.
 3. A tooth paste or gel composition comprising a humectant; anabrasive compound; and an antibacterial effective amount of a compoundrepresented by formula (I)


4. The composition of claim 3, further comprising an anticalculus agent.5. The composition of claim 4, wherein the anticalculus agent comprisesa phosphate compound.
 6. The composition of claim 4, wherein theanticalculus agent comprises tetrasodium pyrophosphate and trisodiumpolyphosphate.
 7. The composition of claim 4, wherein the anticalculusagent comprises a synthetic anionic polycarboxylate.
 8. The compositionof claim 3, further comprising a maleic anhydride copolymer with methylvinyl ether.
 9. The composition of claim 3, comprising tetrasodiumpyrophosphate and trisodium polyphosphate in a weight ratio of about1:7.
 10. The composition of claim 1, further comprising an agentselected from triclosan, delmopinal, cetyl pyridinium chloride, a zinciron source, a stannous ion source, an anti-inflammatory agent andbotanical agents.
 11. A method for inhibiting bacterial growth in theoral cavity comprising applying to the surfaces of the oral cavity acomposition comprising a compound represented by formula (I):


12. The method of claim 10, wherein applying comprises brushing theteeth.
 13. The method of claim 10, wherein the composition furthercomprises a maleic anhydride copolymer with methyl vinyl ether.
 14. Themethod of claim 10, wherein the composition further comprises an agentselected from an anticalculus agent, a phosphate compound, tetrasodiumpyrophosphate and trisodium polyphosphate.
 15. The method of claim 11,further comprising an agent selected from triclosan, delmopinal, cetylpyridinium chloride, a zinc iron source, a stannous ion source, ananti-inflammatory agent and botanical agents.
 16. A method of treatinggingivitis, periodontal disease, and/or ameliorating oral malodorcomprising topically administering a dentifrice composition to thesurface of the oral cavity, the dentifrice composition comprising anantibacterial effective amount of a compound represented by formula (I):


17. The method of claim 16, wherein the compound represented by formula(I) is present in the composition in an amount of about 0.001% to about10% by weight.
 18. The method of claim 16, wherein he compositionfurther comprises an agent selected from triclosan, delmopinal, cetylpyridinium chloride, a zinc iron source, a stannous ion source, ananti-inflammatory agent and botanical agents.